2-carbamido and thiocarbamido oxazoles

ABSTRACT

2-CARBAMIDO AND THIOCARBAMIDOOXAZOLES OF THE FORMULA   2-(R-NH-C(=Y)-NH-),4-R1,5-R2-OXAZOLE   WHERE Y IS O OR S AND R IS HYDROGEN, ALKYL OR ARYL AND R1 AND R2 ARE H, ALKYL, ARYL, CF3, CARBALKOXY OR CARBOXAMIDO; ARE PREPARED BY REACTING A 2-AMINOOXAZOLE WITH AN ARYL OR ALKYL ISOCYANATE OR ISOTHIOCYANATE. THE CARBAMIDO AND THIOCARBAMIDOOXAZOLES ARE USEFUL IN ALLEVIATING INFLAMMATION IN WARM-BLOODED MAMMALS AND THE THIOCARBAMIDOOXAZOLES ARE PARTICULARLY USEFUL IN METHOD FOR CONTROLLING FUNGUS INFECTIONS IN PLANTS.

United States Patent 3,705,903 Z-CARBAMIDO AND THIOCARBAMIDO OXAZOLESGeorge Crank, Engadine, New South Wales, Australia, assignor to LillyIndustries, Ltd.

No Drawing. Continuation-impart of abandoned application Ser. No.53,982, July 10, 1970. This application Nov. 9, 1970, Ser. No. 88,085

Claims priority, application Great Britain, July 22, 1969,

36,859/69; Nov. 5, 1969, 54,290/69 Int. Cl. C07d 85/44 US. Cl. 260307 R12 Claims ABSTRACT OF THE DISCLOSURE Z-carbamido andthiocarbamidooxazoles of the formula l N Y 1 H u H R. o N-C-N-R where Yis O or S and R is hydrogen, alkyl or aryl and R and R are H, alkyl,aryl, (3P carbalkoxy or carboxamido; are prepared by reacting aZ-aminooxazole with an aryl or alkyl isocyanate or isothiocyanate. Thecarbamido and thiocarbamidooxazoles are useful in alleviatinginflammation in warm-blooded mammals and the thiocarbamidooxazoles areparticularly useful in method for controlling fungus infections inplants.

CROSS-R-E-FERENCE TO RELATED APPLICATIONS This application is acontinuation-in-part of my copending application Ser. No. 53,982, filedJuly 10, 1970, and now abandoned.

SUMMARY This invention relates to novel chemical compounds havingvaluable fungicidal and antiinflammatory properties. In particular, itrelates to 2-oxazolylthioureas and 2-oxazolylureas represented by thefollowing formula wherein Y is an oxygen atom or a sulfur atom, R ishydrogen, C -C alkyl, C -C cycloalkyl, allyl, phenyl, benzyl,B-phenethyl, naphthyl or substituted phenyl, and R and R are the same ordifferent and represent hydrogen, C -C lower alkyl, trifluoromethyl,carbalkoxy, carboxamido, phenyl or substituted phenyl, and when Y is asulfur atom R and R are other than carbalko-xy and carboxamido.

The 2-oxazolyl urea and thiourea compounds described herein are preparedby the reaction of Z-aminooxazole or a substituted 2-aminooxazole withan alkyl or aryl isocyanate or an alkyl or aryl isothiocyanate.Alternatively, the 2-isocyano or 2-isothiocyano derivative of oxazole orof a substituted oxazole is reacted with an alkyl or aryl amine to forma compound of the invention.

The 2-oxazolylthiourea compounds described herein inhibit the growth ofmicroorganisms which are pathogenic to animal and plant life. Inparticular the thiourea compounds of this invention are highly effectiveantifungal agents useful for the control of plant pathogens, for examplePiricularia oryzae, Phytophtora infestans, Collelotrichum lagenarz'um,Helminthosporum sativum and Botrytis cinerea, the causative organisms ofrice blast, tomato late blight, anthracnose of cucumbers, leaf spot ofbarley and gray mold of grapes respectively.

The compounds of the invention, both ureas and thioureas, are usefulanti-inflammatory agents in that they 3,705,903 Patented Dec. 12, 1972alleviate the symptoms associated with the inflammatory process inmammalian tissue.

DETAILED DESCRIPTION The antimicrobial and antiinflammatory 2-oxazolylureas and thioureas of the present invention are'characterized by thestructural features of a S-membered heterocyclic oxazole ringsubstituted in the 2-position with a carbamido, thiocarbamido or analkyl or aryl substituted carbamido or thiocarbamido group, and in the 3and/or 4-position with an aryl, alkyl, carbalkoxy or carboxarnido group.

The following structural formula represents the compounds of theinvention:

wherein Y is an oxygen atom or a sulfur atom, R is hydrogen, C C alkyl,C -C cycloalkyl, allyl, phenyl, benzyl, B-phenethyl, naphthyl orsubstituted phenyl, R and R are the same or diflerent and representhydrogen, C -C lower alkyl, trifluoromethyl, carbalkoxy, carboxamido,phenyl or substituted phenyl and when Y is a sulfur atom R and R areother than carbalkoxy and carboxamido.

The term C -C alkyl as used herein refers to the straight and branchedaliphatic hydrocarbons chains such as methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, tert-butyl, n-amyl, n-hexyl, n-heptyl,n-octyl, iso-octyl, nnonyl, n-decyl, n-undecyl, dodecyl and the like. C-C lower alkyl refers to the straight or branched aliphatic hydrocarbonchains containing up to 4 carbon atoms such as those enumerated in thepreceding definition. The term substituted phenyl refers to phenylsubstituted at one or more positions by C -C lower alkyl, C -C loweralkoxy, halogen, trifiuoromethyl or nitro and includes, 4- methylphenyl,3,4-dimethylphenyl, 4-isopropylphenyl, pnitrophenyl, 3,4 dichlorophenyl,4 sec-butylphenyl, pmethoxyphenyl, 3 methoxy-4-ethoxyphenyl,3-trifluoromethylphenyl, 4 isopropoxyphenyl, 3 bromophenyl, 4-fluorophenyl, 3,5 dimethylphenyl and like substituted phenyl groups.Naphthyl refers to both a-naphthyl and naphthyl. Carbalkoxy refers tothe C -C alkoxy carbonyl radicals such as methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl and the like andcarboxamido refers to the primary carboxylic acid amide function and theC -C lower alkyl substituted carboxylic acid amide function for example,N,N-dimethylcarboxamido, N-ethylcarboxamido, N,N-di(n-butyl-carboxamidoand the like. The term halogen as used herein refers to fluoro, chloro,bromo and iodo, chloro and bromo representing preferred species.

The 2-oxazolyl urea and thiourea compounds represented by the aboveformula are prepared by the reaction of 2-aminooxazole or a substitutedZ-aminooxazole with an alkyl or aryl isocyanate or isothiocyanateaccording to the following equation.

wherein Y, R, R and R have the same meanings as previously assigned. Thereaction is carried out by heating equimolar amounts of the aminooxazoleand isothiocyanate or isocyanate in a substantially dry, unreactivesolvent such as toluene, xylene, pyridine or other suitable solvent.Generally the reaction mixture is heated to the reflux temperature andrefluxed for about 4 to 20 hours. The Z-oxazolyl thiourea or ureareaction product is isolated by evaporating the reaction mixture toremove solvent and extracting the product from the residue with asolvent such as ethanol. The ethanolic extract containing the reactionproduct can be decolorized, if necessary, by boiling the extract withcharcoal. The clarified extract is evaporated to a lesser volume untilthe product commences to crystallize. The 2-oxazolyl thiourea or ureathus obtained can be further purified if desired by recrystallizationfrom ethanol or other suitable solvent.

Alternatively, the compounds of this invention can be prepared by thereaction of Z-isothiocyanooxazole, 2-isocyanooxazole, or a derivativethereof with an alkyl or aryl amine as shown in the following equation,

wherein Y, R, R and R have the same meanings as defined previously. Thisalternative method of preparing the compounds of the invention iscarried out generally in the same manner as the previously discussedpreparative method. For example, the Z-isothiocyano oxazole orisocyanooxazole is reacted with an equimolar amount of the appropriatealkyl or aryl amine in a solvent such as toluene at the refluxtemperature of the reaction mixture. The Z-oxazolyl thiourea or ureareaction product is isolated from the reaction mixture in essentiallythe same manner as described in the preceding method.2-isothiocyanooxazole or Z-isocyanooxazole can be prepared fromZ-aminooxazole by employing a conventional method for the synthesis ofisothiocyanates or isocyanates as for example, by the reaction of2-aminooxazole with thiophosgene or phosgene.

The preferred method for the preparation of the compounds of theinvention is the former described method which employs the reaction of aZ-aminooxazole with an alkyl or an aryl isothiocyanate or isocyanate.

The following compounds are representative of the compounds of theinvention described by the foregoing general formula:

Z-oxazolyl thiourea 1-methyl-3-.(2-oxazolyl) thiourea l-ethyl-3-(2-oxazolyl) thiourea l-methyl-3- [4- 3,4'-xylyl -2-oxazolyl] thioureal-methyl-3- S-p-chlorophenyl-2-oxazolyl) thiourea 1-ethyl-3-4-p-trifluoromethylphenyl-Z-oxazolyl thiourea 1-methyl-3-(4-p-trifluoromethylphenyl-2-oxazolyl) thiourea 1-n-propyl-3- 2-oxazolylthiourea l-isopropyl-3-.( 2-oxazolyl) thiourea l-n-butyl-3- (2-oxazolylthiourea 1-iso-butyl-3- (2-oxazolyl) thiourea l-n-amyl-3- (2-oxazolyl)thiourea 1-n-hexyl-3 2-oxazolyl thiourea 1-n-heptyl-3- (2-oxazolylthiourea 1-n-octyl-3- 2-oxazolyl) thiourea 1-iso-octyl-3 2-oxazolylthiourea 1-ndecyl-3- (2- oxazolyl thiourea 1-n-dodecyl-3- (2-oxazolylthiourea 1-(4,S-dimethyl-2-oxazolyl thiourea l-methyl-3-4-methyl-2-oxazolyl) thiourea l-cyclohexyl-B 2-oxazolyl) thiourea I-cyclopentyl-3- 2-oxazolyl) thiourea l-methyl-3-,( 4, 5-dimethyl-2-oxazolyl thiourea 1-n-butyl-3 4,5 -dimethyl-2-oxazolyl)thiourea l-methyl-3- 4-n-propyl-2-oxazolyl thiourea l-allyl-3-2-oxazolyl) thiourea l-allyl-3- 4,5 -dime thyl-2-oxazolyl) thiou real-phenyl-3- 2-oxazolyl) thiourea 1-p-tolyl-3- (Z-oxazolyl) thio urea1-,(4-chlorophenyl) -3- (2-oxazolyl) thiourea 1-benzyl-3 (2-oxazolyl)thio urea 1- (4-trifluoromethylphenyl) -3- 2-oxazolyl) thiourea 1-(4-n-butylphenyl) -3- (Z-oxazolyl) thiourea 1- 4-isopropylphenyl) -3-(2-oxazolyl) thiourea 1- 4-cfluorophenyl -3 2-oxazolyl) thiourea 1-3-bromophenyl) -3 2-oxazolyl) thiourea l- 4-ethylphenyl) -3-(4-n-butyl-2-oxazolyl) thiourea 2-oxazolyl urea l-methyl-3 2-oxazolylurea 1-n-butyl-3 (2-oxazolyl)urea 1-phenyl-3- (4-methyl-2-oxazolyl) ureal-ot-naphthyl-3- 4, 5 -dimethyl-2-oxazolyl) urea.

1-p-tolyl-3-(2-oxazolyl) urea l3-phenethy1-3-(4-p-chlorophenyl-2-oxazolyl urea l-methyl-3- (4,5-dicarbethoxy-Z-oxazolyl) urea1-ethyl-31(4-ethyl-S-carbomethoxyQ-oxazolyl)urea1-phenyl-31(4-carboxamido-2-oxazolyl) urea 1-n-butyl-3- 4,5-diethyl-2-oxazolyl )urea 1-iso-propyl-3-4-N,N-diethylcarboxamido-Z-oxazolyl) urea l-allyl-3 2-oxazolyl )urea l-benzyl-3- 4,5 -diethyl-2-oxazolyl) urea 1- 4-methoxyphenyl) -3-.( 4, 5-diphenyl-2-oxazolyl ureal-methyl-3-(4-p-bromophenyl-S-carboethoxy-Z-oxazolyl) urea l-(4-ethylphenyl) -3- (2-oxazolyl urea 1-n-hexyl-3-(4,5-dimethyl-2-oxazoly1) urea 1- (o-tolyl 3-.(4-p-chlorophenyl-Z-oxazolyl) urea 4,5 -diphenyl-2-oxazolyl urea and thelike.

As previously mentioned, the Z-oxazolyl thiourea compounds of thisinvention are fungicidally active and are useful for the control offungi pathogenic to economically important plant life.

Table I which follows contains the test results obtained withrepresentative 2-oxazolyl thioureas in standard foliar fungicide tests.As shown, the compounds display significant fungicidal activity againstthe diseases tomato late blight, rice blast, anthracnose of cucumber andHelminthosporum leaf spot of barley.

The results shown were obtained in tests carried out as described in thefollowing paragraphs. In each test the compound was formulated as anaqueous emulsion or solution at a concentration of 400 p.p.m. andapplied as a foliar spray.

Rice blast: The aqueous emulsion of the test compound was applied to allleaf surfaces of l4-day-old rice plants of the NATO variety and allowedto dry. The foliage was then inoculated with a water suspension ofconidia (Piricularia oryzae race N-l) by means of a sprayer. The treatedplants were placed in a moist chamber at 65 F. for 40 hours before beingreturned to the greenhouse. Eight days thereafter, the symptoms of theblast disease were observed and compared with control plants.

Cucumber anthracnose: The aqueous emulsion of the test compound wassprayed on all leaf surfaces of 15- day-old cucumber plants (greenProlific variety) and allowed to dry. The foliage was then inoculatedwith a Water suspension of conidia (Collectotrichum lagenarium) by meansof a sprayer.

Following inoculation, the treated plants were placed in a moist chambermaintained at 75 C. for 40 hours after which the plants were returned tothe greenhouse. On the tenth day following treatment and inoculation thesymptoms were observed and recorded and compared with control plants.

Tomato late blight: The aqueous emulsion of the test compound wassprayed on all leaf surfaces of 28 day old tomato plants of the BonnieBest variety and allowed to dry. The plants were then inoculated with awater suspension of fungal propagules (Phytophthora infestans) by meansof a sprayer. The plants were placed in a moist chamber maintained at atemperature of 65 F. for 24 hours after which they were returned to thegreenhouse. Three days thereafter, the symptoms of late blight diseasewere observed and recorded and compared with control plants.

Helminthosporum leaf spot of barley: The aqueous emulsion of the testcompound was sprayed on 6 day old barley seedlings 4-5 inches tall ofthe Larker variety and allowed to dry. The plants were then inoculatedwith an aqueous suspension of spores of Helminthosporum sativum andplaced in a moist chamber at 65 F. for 48 hours. Two days later theplants were removed from the chamber and placed in the greenhouse. Fourdays thereafter, or twelve days from planting, the symptoms of leaf spotdisease were observed and recorded and the results were compared withcontrol plants.

TABLE I.FUNGICIDAL ACTIVITY OF Z-OXAZOYL THIOUREAS Activity rating 1 at400 p.p.m. vs.

Cucum- Tomato Barley Rice ber anthraclate leaf bla nose blight spotCompound name l Activity rating: 1=No control; 2= Slight control; 3=Moderate control; 4= Good control; 5=Complete control.

an:- tmmbw cacao: a cum:- P O! s-cn lew-zmpm c-cl unawwa N HM bDwNt-oowv- M wrote an eov cow-use: coat-- on new a: w-

The 2-oxazolyl thioureas described herein are also useful in combatinginfections caused by the organism Botrytis cin'erea, for example, graymold of grapes.

The 2-oxazolyl thioureas also possess significant activity against RootKnot nematodes.

The fungicidally active 2-oxazolyl thioureas can be employed for theprotection of plants susceptible to pathogenic fungi and thereby preventthe onset of disease symptoms. They can likewise be used in thetreatment of infected plants. When so used, the 2-oxazolyl thioureas canbe formulated as a solution, emulsion or emulsifiable concentrate, or asa dust, however, they are preferably formulated as a solution suitablefor foliar spray application. Aqueous solutions of the 2-oxazolylthioureas at concentrations of from about 100 to about 1000 ppm. can beprepared with the aid of a solubilizing agent and are useful fungicidalspray solutions when applied to the foliage of susceptible plants.Likewise, aqueous emulsions of the compounds of the invention can beprepared in similar concentrations with the aid of an emulsifier and asolubilizing agent. The aqueous solutions and emulsions desirablycontain a wetting agent to enhance the spreadability of the formulationsover the leaf surface. Suitable emulsifying agents can be of the ionicor non-ionic types, such as the condensation products of alkylene oxideswith phenols and organic acids, polyoxyethylene derivatives of sorbitanesters, aral'kyl and alkyl sulfonates and the like.

Concentrated dust formulations can be prepared by incorporating fromabout to about 25 percent of a 2- oxazolyl thiourea compound in a finelydivided inert, solid carrier such as diatomaceous earth, fullers earth,bentonite, talc, and the like. Such dust formulations can be useddirectly or they can be further diluted with inert carrier to achievelower concentrations of the oxazolyl thiourea compound.

The 2-oxazolyl thioureas of this invention also possess usefulanti-bacterial activity against both gram-negative and gram-positivebacteria, particularly the latter. For example, the minimum inhibitoryconcentrations of compounds of the invention against Aerobacteraerogenes, Brucella bronchineptica, Escherichia coli, Klebsiellaaerogenes, and Salmonella typhimurium normally lie between 16 and 64,ug/ml. whilst the minimum inhibitory concentrations againstgram-positive bacteria such as Staphylococcus aureus and Streptococcusfaecalis normally lie between 2 and 16 ig/ml.

Accordingly, the present invention provides a method of treatingbacterial infections in animals which method comprises administering tothe animal an effective nontoxic dose of a 2-oxazolyl thiourea of thisinvention. The dose administered will normally lie between 5 to 150 mg./kg. although it will be appreciated that the dose may lie outside theselimits and will depend on a variety of factors including the conditionof the patient, the infection being treated and its severity. Thecompounds may be used externally or internally, for example orally, andfor this purpose they will normally be formulated into a suitablecomposition form comprising the active compound and a pharmaceuticallyacceptable carrier therefor. The compositions may take the form oftablets, capsules, powders, injection, solutions and the like, as iswell known in the pharmaceutical art.

Both the urea and thiourea compounds of this invention exhibitantiinflammatory activity when administered parenterally or orally towarm blooded mammals. Accordingly, they are useful in the treatment ofinflammation of mammalian tissue and especially for alleviating thediscomforting symptoms related thereto such as fever, sensitivity to thetouch, swelling and pain. The 2-oxazolyl ureas, being somewhat moreactive, are preferred and are effective in alleviating and controllinginflammation in warm-blooded mammals when administered orally at a dailydose of about 25 mg./kg. to about 150 mg./kg. of body weight. Thecompounds of the invention can be formulated for oral administration inany of the commonly employed oral dosage formulations such as tablets,capsules or liquid suspensions. -In such dosage form the compounds canbe suitably formulated with a pharmaceutically acceptable carrier as forexample in tablet form with glucose, starch and a binding agent.

The compounds of the invention can be administered as a single dailydose or preferably as multiple smaller doses throughout the day, forexample 2 to 6 times daily. The level of dose required as well as theduration of treatment with any particular host is dependent on a varietyof factors such as the intensity and extent of the inflammation, thetype of tissue involved in the inflammatory process, the general healthof the host and the origin of the inflammation.

This invention is more fully illustrated by the following examples.

EXAMPLE 1 product was filtered to yield 3.2 g. of 1-methyl-3-(2-.

oxazolyl)thiourea as white crystals melting at about 176 C. afterrecrystallization from chloroform.

Elemental analysis for C H N OS.'Iheory (percent): C, 38.2; H, 4.5; N,26.7. Found (percent): C, 38.0; H, 4.5; N, 26.8.

In a similar manner the following compounds were prepared by thereaction of 2-aminooxazole with the indicated isothiocyanate:

1-ethyl-3-(2-oxazolyl)thiourea melting at about 127 C.,

was prepared with ethyl isothiocyanate;

1-n-propyl-3-(2-oxazolyl)thiourea, melting at about 126 C. was preparedwith n-propyl isothiocyanate;

1-iso-propyl-3-(2-oxazolyl)thiourea, melting at about C., was preparedwith iso-propyl isothiocyanate;

1-n-butyl-3-(2-oxazolyl)thiourea, melting at about 121 C. was preparedwith n-butyl isothiocyanate; 1-n-amyl-3-(2-oxazolyl)thiourea melting atabout 77 C.

was prepared with n-amyl isothiocyanate;1-n-octy1-3-(2-oxazolyl)thiourea, melting at about 96 C.,

was prepared with n-octyl isothiocyanate;1-iso-butyl-3-(2-oxazolyl)thiourea, melting at about 140 C., wasprepared with iso-butyl isothiocyanate; 1-allyl-3-(2-oxazolyl)thiourea,melting at about 85 C.

was prepared with allyl isothiocyanate; 1-benzyl-3-(2-oxazolyl)thiourea,melting at about 138 C., was prepared with benzyl isothiocyanate;l-phenyl-3-(2-oxazolyl)thiourea, melting at about 265 C., was preparedwith phenyl isothiocyanate; l-fi-phenethyl-3-(2-oxazolyl)thiourea,melting at about 130 C., Was prepared with p-phenylethyl isothiocyanate;1-cyclohexyl-3-(2-oxazolyl)thiourea, melting at about 143 C., wasprepared with cyclohexyl isothiocyanate.

EXAMPLE 2 To 75 ml. of dry toluene were added 5.6 g. of 2- amino-4,5-dimethyloxazole and 3.65 g. of methyl isothiocyanate and thereaction mixture was heated at the reflux temperature for 20 hours. Thetoluene was removed from the reaction mixture by evaporation and theresidue was extracted with ethanol. The ethanol extract was clarifiedwith charcoal and reduced in volume by evaporation until crystallizationof the reaction product commenced. The crystalline product was filteredand dried to yield 4.1 g. of1-methyl-3-(4,5-dimethyl-2-oxazolyl)thiourea as pale yellow crystalsmelting at about 168 C. after recrystallization from ethanol.

Elemental analysis for C H N OS.-Theory (percent): C, 45.40; H, 5.98; N,22.68. Found (percent): C, 45.44; H, 5.71; N, 22.93.

In a similar manner the following compounds were prepared by thereaction of 2 amino 4,5 diphenyloxazole with the indicatedisothicyanate:

l-n-propyl-3-(4,5-dimethyl 2 oxazolyl)thiourea melting at about 133 C.,was prepared with n-propyl isothiocyanate;

1-allyl-3-(4,5-dimethyl 2 oxazolyl)thioure a, melting at about 150 C.,was prepared with allyl isothiocyanate.

In a similar manner the following compounds were prepared by thereaction of 2-amino-4,5-diphenyloxazole with the indicatedisothiocyanate:

1-methyl-3-(4,5-diphenyl2-oxazolyl)thiourea, melting at about 230 C.,was prepared with methyl isothiocyanate.

1-ethyl-3-(4,5-diphenyl-2-oxazolyl)thiourea, melting at about 198 C.,was prepared with ethyl isothiocyanate.

Similarly by reaction of 2-amino-4-methyloxazole with methylisothiocyanate and 2-amino-4-trifluoromethyloxazole with ethylisothiocyanate, there were obtained respectively:

l-methyl-3-(4-methyl 2 oxazolyl)thiourea melting at about 192 C., andl-ethyl-3-(4-triiluoromethyl-2-oxazolyl) thiourea melting at about 172C.

EXAMPLE 3 To a solution of 2.52 g. (0.02 mole) of 2-isothiocyanooxa'zolein ml. of toluene was added 0.62 g. (0.02 mole) of methylarnine and thereaction solution refluxed for 16 hours. The toluene was removed byevaporation and the residue extracted with ethanol. The ethanol extractwas charcoaled and evaporated until crystallization of the productcommenced. After filtration and recrystallization from chloroform,l-methyl-3-(2-oxazolyl) thiourea was obtained. The product was identical(MP. and mixed M.P.) with that obtained by the process of Example 1.

Similarly, the other products obtained in Examples 1 and 2, wereprepared by the process of this example.

EXAMPLE 4 A solution of 3.36 g. of Z-aminooxazole and 2.84 g. of ethylisocyanate in 30 ml. of dry toluene was heated at the reflux temperaturefor 2 hours and was then treated with charcoal. The Warm reactionmixture was then filtered and concentrated in vacuo to yield 2.75 g. ofl-ethyl-3-(2-oxazolyl)urea as a white crystalline solid melting at about163-164 C. after recrystallization from toluene.

Elemental analysis for C H N O .-Theory (percent): C, 46.4; H, 5.8; N,26.9. Found (percent): C, 46.2; H, 5.8; N, 27.1.

In a similar manner the following compounds were prepared by thereaction of Z-aminooxazole with the designated isocyanate:

l-n-propyl-3-(2-oxazolyl)urea melting at about 146 C. was prepared withn-propyl isocyanate.

Elemental analysis for C H ,N-,-O .Theory (percent): C, 49.7; H, 6.5; N,24.9. Found (percent): C, 49.6; H, 6.8; N, 25.0.

1-isopropyl-3-(2-oxazolyl)urea melting at about 139- 140 C. was preparedwith isopropyl isocyanate and recrystallized from carbon tetrachloride.

Elemental analysis for C H N O .Theory (percent): C, 49.7; H, 6.5; N,24.9. Found (percent): C, 49.7; H, 6.6; N, 25.1

1-n-butyl-3-(2-oxazolyl)urea melting at about 130- 131 C. was preparedwith n-butyl isocyanate and recrystallized from chloroform.

Elemental analysis for C H N O' .Theory (percent): C, 52.4; H, 7.1; N,22.9. Found (percent): C, 52.2; H, 7.0; N, 22.8.

1-phenyl-3-(2-oxazolyl)urea melting at about 164-165 C. was preparedwith phenyl isocyanate and recrystallized from toluene.

'Elemental analysis for C ,,H N O .'Iheory (percent): C, 59.2; H, 4.5;N, 20.7. Found (percent): C, 59.3; H, 4.7; N, 20.6.

l-(p chlorophenyl) 3 (2 oxazolyl)urea melting at about 169-17l C. wasprepared with p-chlorophenyl isocyanate and recrystallized fromchloroform.

Elemental analysis for C H N O Cl.--Theory (percent): C, 50.5; H, 3.4;N, 17.7; C1, 14.9. Found (percent): C, 50.2; H, 3.6; N, 17.6; C1, 15.1.

l-(m chlorophenyl) 3 (2 oxazolyl)urea melting at about 162163 C. wasprepared with m-chlorophenyl isocyanate and recrystallized fromchloroform.

Elemental analysis for C H N O Cl.-Theory (percent): C, 50.5; H, 3.4; N,17.7; CI, 14.9. Found (percent): C, 50.4; H, 3.6; N, 17.6; C1, 15.0.

1-(0 chlorophenyl) 3 (2 oxazolyl)urea melting at about 170-172 C. wasprepared with o-chlorophenyl isocyanate and was recrystallized fromcarbon tetrachloride.

Elemental analysis for C H N O' Cl.Theory (percent): C, 50.5; H, 3.4; N,17.7; C1, 14.9. Found (percent): C, 50.4; H, 3.5; N, 17.4; Cl, 15.2.

1-(o-tolyl)-3-(2-oxazolyl)urea melting at about 166 C. was prepared witho-tolyl isocyanate and was recrystallized from carbon tetrachloride.

Elemental analysis for C H N O .-Theor"y (percent): C, 60.8; H, 5.1; N,19.3. Found (percent): C, 61.1; H, 5.3; N, 19.5.

l-(p-nitrophenyl)-3-(2-oxazolyl)urea melting at about 238 C. d. (yellowsolid) was prepared with p-nitrophenyl isocyanate and was recrystallizedfrom ethanodimethylformamide.

Elemental analysis for C H N O.,.-Theory (percent): C, 48.4; H, 3.2; N,22.6. Found (percent): C, 48.7; H, 3.5; N, 22.4.

1-(a-naphthyl)-3-(2-oxazolyl)urea melting at about 257259 C. wasprepared with a-naphthyl isocyanate and was recrystallized from toluene.

Elemental analysis for C H N O .Theory (percent): C, 66.4; H, 4.4; N,16.6. Found (percent): C, 66.7; H, 4.6; N, 16.4.

EXAMPLE 5 A solution of 9.4 g. of 2-amino-4,S-diph enyloxazole and 6.17g. of phenyl isocyanate in 12 5 ml. of toluene was heated for 1.5 hoursat the refiux temperature. The reaction mixture was evaporated todryness and the solid residue was purified by recrystallization fromchloroform to yield 4.68 g. of 1-phenyl-3-(4,5-diphenyl-2-oxazolyl) ureaas a white crystalline solid melting at about 211- 213 C.

Elemental analysis for C H N O .Theory (percent): C, 74.4; H, 4.9; N,11.9. Found (percent): C, 74.4; H, 4.8; N, 11.8.

In a similar manner the following compounds were prepared by thereaction of 2-amino-4,5-diphenyloxazole with the indicated isocyanate:

1 (m-chlorophenyl)-3-(4,5-diphenyl-2-oxazolyl)urea melting at about205207 C. was prepared with m-chlorophenyl isocyanate and wasrecrystallized from chloroform.

Elemental analysis for C H N ClO .The0ry (percent): C, 67.8; H, 4.3; N,10.9; Cl, 9.3. Found (percent): C, 67.8; H, 4.1; N, 10.8; C1, 9.1.

1 ethyl-3-(4,5-diphenyl-2-oxazolyl)urea melting at about 181-182 C. wasprepared with ethyl isocyanate and was recrystallized from carbontetrachloride.

Elemental analysis for C H N O .Theory (percent): C, 70.2; H, 5.6; N,13.9. Found (percent): C, 70.4; H, 5.6; N, 13.7.

EXAMPLE 6 A solution of 7.84 g. of 2-amino-4,S-dirnethyloxazole and 10.7g. of o-chlorophenyl isocyanate in 300 ml. of toluene was heated for 2.5hours at the reflux temperature. The reaction mixture was thenevaporated to dryness and the solid residue was purified byrecrystallization from chloroform to yield 5.35 g. of1-(0-chlorophenyl)-3- (4,5-dimethyl-2-oxazolyl)urea as white crystalsmelting at about 167168 C.

Elemental analysis for C H ClN O .Theory (percent): C, 54.25; H, 4.5;Cl, 13.3; N, 15.8. Found (percent): C, 53.75; H, 4.6; Cl, 13.7; N, 16.0.

In a similar manner the following compounds were prepared by thereaction of 2-amino-4,S-dimethyloxazole with the indicated isocyanate:

1 (m-chlorophenyl)-3-(4,S-dimethyl-Z-oxazolyl)urea melting at about164165 C. was prepared with m-chlorophenyl isocyanate and wasrecrystallized from chloroform.

Elemental analysis for C H ClN O .-The0ry (percent): C, 54.25; H, 4.6;Cl, 13.3; N, 15.8. Found (percent): C, 54.0; H, 4.7; Cl, 13.5; N, 15.8.

1 (p-chlorophenyl) 3-(4,5-dimethyl-2-oxazolyl)urea melting at about190-191 C. (pale yellow crystalline 10 solid) was prepared withp-chlorophenyl isocyanate and was recrystallized from chloroform.

Elemental analysis for C H ClN O .--Theory (percent): C, 54.25; H, 4.6;N, 15.8; C1, 13.3. Found (percent): C, 54.2; H, 4.5; N, 15.8; Cl, 13.3.

EXAMPLE 7 A solution of 1.96 g. of 2-amino-4-methyloxazole and 1.42 g.of ethyl isocyanate in 20 ml. of toluene was heated for 2 hours at thereflux temperature. The reaction mixture was then evaporated to drynessto yield 1.6 g. of 1- ethyl-3-(4-methyl-2-oxazolyl)urea as an oilyresidue which crystallized on standing. The crystalline product wasrecrystallized from carbon tetrachloride and melted at about 132134 C.

Elemental analysis for C H N O .Theory (percent): C, 49.7; H, 6.6; N,24.8. Found (percent): C, 49.9; H, 6.5; N, 25.1.

I claim:

1. A compound of the formula wherein Y is an oxygen or sulfur atom, R isC -C cycloalkyl, allyl, phenyl, benzyl, fl-phenethyl, naphthyl,halophenyl, C -C lower alkyl phenyl, nitrophenyl, ortrifluoromethyphenyl; R and R are the same or different and representhydrogen, C C, lower alkyl, or phenyl.

2. The compound of claim 1 wherein Y is sulfur.

3. The compound of claim 1 wherein Y is oxygen.

4. The compound of claim 2, said compound being 1- phenyl-3- 2-oxazolylthiourea.

5. The compound of claim 2, said compound being 1-benzyl-3-(2-oxazolyl)thiourea.

6. The compound of claim 2, said compound being 1- j3-phenethyl-3-(2-oxazolyl thiourea.

7. The compound of claim 2, said compound being 1-cycloheXyl-3-(2-oxazolyl)thiourea.

8. The compound of claim 2, said compound being 1- allyl-3- (4,5-dimethyl-2-oxazoly1) thiourea.

9. The compound of claim 3, said compound being 1-(p-nitrophenyl)-3-(2-oxazolyl)urea.

10. The compound of claim 3, said compound being 1- phenyl-3(2-oxazolyl) urea.

11. The compound of claim 3, said compound being1-(o-tolyl)-3-(2-oxazolyl)urea.

12. The compound of claim 3, said compound being 1- (p-chlorophenyl) -3-(4,5-dimethyl-2-oxazolyl) urea.

References Cited UNITED STATES PATENTS 3,499,910 3/1970 Driscoll260306.8

ALEX MAZEL, Primary Examiner R. V. RUSH, Assistant Examiner US. Cl. X.R.424-272

